Astrocytes have generally been believed to play a supportive role for neurons in the central nervous system. However, a growing body of evidence suggests that astrocytes actively participate in neuronal processes. Studies have begun linking the role of astrocytes to memory, and previous work from the Alberini lab has implicated astrocyte-neuron lactate transport as critical to memory function. Suzuki et al (2011) observed that during fear conditioning, levels of extracellular lactate increase in the hippocampus. Inhibition of glycogenolysis during fear conditioning, which occurs in astrocytes but not neurons, prevented the increase of lactate and disrupted the long-term fear memory. Notably, disruption of lactate release from astrocytes or the disruption of lactate transport into neurons during training also impaired long-term memory formation. Importantly, injection of lactate or glucose into the hippocampus could rescue the memory, but glucose is not as effective as lactate. For this application, I am requesting two years of funding to continue this line of research. The proposed experiments have been designed to examine the nature and specific contributions of lactate to neuronal function. First, we seek to demonstrate that neurons utilize lactate as an energy source. Since neurons can directly import glucose and lactate, we will test to see if these energy sources are interchangeable, or if lactate and glucose fuel specific processes. We hypothesize that neurons require glucose for basic cellular processes, and utilize lactate during the periods of high activity that occur during a learning event. Further experiments will examine which cellular processes that occur during memory formation are supported by lactate. De novo protein synthesis is required for long-term memory formation, and protein synthesis occurs locally at activated synapses. Protein synthesis is costly in terms of energy, and lactate transport machinery is localized to the synapse. Thus, we will test the hypothesis that local synaptic protein synthesis requires lactate transport from astrocytes into neurons to support memory.